title: An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis.
abstract: Sterol regulatory element-binding proteins (SREBPs) have evolved as a focal point for linking lipid synthesis with other pathways that regulate cell growth and survival. Here, we have uncovered a polycistrionic microRNA (miRNA) locus that is activated directly by SREBP-2. Two of the encoded miRNAs, miR-182 and miR-96, negatively regulate the expression of Fbxw7 and Insig-2, respectively, and both are known to negatively affect nuclear SREBP accumulation. Direct manipulation of this miRNA pathway alters nuclear SREBP levels and endogenous lipid synthesis. Thus, we have uncovered a mechanism for the regulation of intracellular lipid metabolism mediated by the concerted action of a pair of miRNAs that are expressed from the same SREBP-2-regulated miRNA locus, and each targets a different protein of the multistep pathway that regulates SREBP function. These studies reveal an miRNA "operon" analogous to the classic model for genetic control in bacterial regulatory systems.
authors.affiliation: Metabolic Signaling and Disease Program and Diabetes and Obesity Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Tae-Il
authors.initials: TI
authors.lastname: Jeon
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Esquejo
authors.forename: Manuel
authors.initials: M
authors.lastname: Roqueta-Rivera
authors.forename: Peter E
authors.initials: PE
authors.lastname: Phelan
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Moon
authors.forename: Subramaniam S
authors.initials: SS
authors.lastname: Govindarajan
authors.forename: Christine C
authors.initials: CC
authors.lastname: Esau
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Osborne
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D044783:F-Box Proteins / Q000235:genetics / Q000502:physiology; D000073979:F-Box-WD Repeat-Containing Protein 7; D005809:Genes, Regulator / Q000235:genetics* / Q000502:physiology; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics* / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D023421:Models, Animal; D009876:Operon / Q000235:genetics* / Q000502:physiology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C506120:Insig2 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C540524:Mirn182 microRNA, mouse; C541554:Mirn96 microRNA, mouse; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D044767:Ubiquitin-Protein Ligases